The Physiology of Wound Healing

Drawn from “Wound Management to 2026”. Details
See also, “Factors Affecting Wound Healing.”

anatomy of human skin
Anatomy of human skin

When body tissue is damaged by trauma, surgery, hypoxia, or other destructive processes, the body’s physiology of wound healing quickly reacts to protect itself and begin the process of healing. Clean surgical wounds closed by primary intention heal rapidly and do not usually require additional medical intervention and support. Chronic wounds and those left to heal by secondary intention will require more attention from the medical team. Most of the literature describing the phases of wound healing has been written following investigation of clean, acute wounds, and the sequence and timing of the events described thus only relate to acute wounds. It is assumed that the chronic wound follows a similar wound-healing course with the timing of events delayed or prolonged compared with acute wounds.

All wounds must pass through three recognized physiological processes in order to achieve healing: the inflammatory phase, proliferative phase, and maturation phase. It is useful to view the stages of wound healing as distinct events, but in reality, there is overlap between the phases, and an individual wound may be in several phases at the same time. Unlike acute or surgical wounds, which heal by “primary intent” – the joining of the wound edges by sutures, staples, or adhesive strips – skin ulcers and severe burns heal by “secondary intent,” through the formation of granulation tissue, contraction of the wound, and epithelialization. A normal wound heals in about 21 days in organized phases of inflammation, proliferation, and remodeling, but chronic wounds often stall between the inflammatory and proliferation stages, creating wounds that can last for months or even years. It is only when all the stages have been accomplished over the entire wound surface that complete wound healing has been achieved.

Wound healing physiology
Source: Medscape (

Wound healing physiology is also alternatively divided into defensive, proliferative, and maturation; each phase must be allowed to occur without impediment for healing to be complete. The defensive phase occurs from the time of injury to three days and is characterized by hemostasis and inflammation. The clotting cascade is initiated, and white blood cells mobilize to defend and protect the area from bacterial invasion. Vasodilatation and serous exudate facilitate the removal of debris and the delivery of nutrients to injured tissue.

Proliferation lasts from day two until the area is healed and features granulation, contraction, and epithelialization. Granulation includes neo angiogenesis and collagen formation. Granular tissue is pale pink to beefy red, glistening, and has a rough surface due to blood vessels and collagen deposits. Contraction occurs as a result of myofibroblasts pulling collagen toward the cell body, and epithelialization is the migration of epithelial cells to resurface the area.

Maturation is the last phase of healing, and involves scar remodeling after wound closure. This phase may take years. Maturation sees a scar change from red to purple/pink to white, and from bumpy to flat.

Wound management priorities include: 1) reducing or eliminating causative factors (pressure, shear, friction, moisture, circulatory impairment, and/or neuropathy), 2) providing systemic support for healing (blood, oxygen, fluid, nutrition, and/or antibiotics), and, 3) applying the appropriate topical therapy (remove necrotic tissue or foreign body, eliminate infection, obliterate dead space, absorb exudate, maintain moist environment, protect from trauma and bacterial invasion, and provide thermal insulation).

wound market segments globally
Wound treatments are myriad.

The diversity of wounds and wound care products complicates the dressing selection process; many wounds have several options for dressings that are effective. Matching wound characteristics with dressing features is one important goal in the wound care and healing process. For example, a heavily exuding wound needs an absorptive dressing, and a wound with necrotic eschar needs a dressing that facilitates debridement. Dressings fall into several categories: gauze, hydrogel, hydrocolloid, transparent film, alginate, foam, and accessory products such as enzymes, growth factors, biological dressings, compression devices, support surfaces, and methods for securing dressings.

Factors affecting healing include tissue perfusion and oxygenation, presence or absence of infection, nutrition, medications, underlying disease, mobility and sensation, and age. Circulation and adequate oxygen saturation deliver nutrients for wound healing and gas exchange. All wounds disrupting the integument are contaminated, but not necessarily infected. Bacteria compete with tissues for nutrients, prolonging the inflammatory stage and delay collagen synthesis and epithelialization. Vitamin C, the B vitamins, zinc, and copper are necessary for collagen synthesis. Vitamin A combats the effects of steroids and protein is needed for collagen and skin growth. Steroids and immunosuppressive drugs suppress the inflammatory phase thus slowing the entire healing process. Underlying chronic disease(s) also competes for nutrients, increases risk of infection, and stresses the healing process. Limited mobility and/or sensation contribute to wound formation and impair the perception of wound presence or complications.

Debridement is necessary when necrotic eschar or fibrinous slough is present in the wound base. Necrotic eschar is thick, leathery, devitalized, black tissue, and slough is white or yellow tenuous tissue. Methods of debridement are described as sharp (surgical), mechanical (dressings), autolytic (dressings) and enzymatic (enzymes). Sharp debridement is indicated for extensive necrosis or for large wounds. Mechanical and autolytic debridement is indicated for many pediatric wounds and is accomplished with dressings. Mechanical debridement is done with a wet to dry dressing using woven gauze; as wet fibers dry, tissue adheres to the fiber and is removed when the dressing is removed. Autolytic debridement is also indicated for many pediatric wounds and is done with an occlusive dressing that retains moisture on the wound and allows white blood cells and enzymes to break down necrotic tissue. Hydrocolloids, transparent films, and hydrogels are effective for autolytic debridement. Enzymatic debridement is indicated when selective debridement is desired because enzymes only work on necrotic tissue. Enzymatic preparations contain fibrinolysin, collagenase, papain or trypsin in a cream or ointment base. Enzymatic debridement is slow, but effective, and instructions for using enzymes must be followed closely.

Wound cleansing removes dressing residue, microbes, and cellular debris (may include healing tissue). Cleansing products need to be safe for healing tissue and effective at removing debris. The adage “don’t put anything in a wound you wouldn’t put in your eye” are safe words to work by. Many topical cleansing agents and antiseptics are cytotoxic, and it is imperative to weigh the risks of cytotoxicity against the benefits of cleansing effectiveness and antimicrobial activity.

Normal saline is safe, effective, readily available, and inexpensive. Wound irrigation pressure needs to be high enough to remove debris and low enough to avoid traumatizing tissue. Pressures ranging from 4-15 pounds per square inch (psi) are effective for cleaning. For example, a 60cc catheter tip syringe delivers 4.2 psi, a 35cc syringe with a 19-gauge needle delivers 8.0 psi, and a Water Pik at its highest setting delivers >50 psi. Frequency of wound cleansing varies with wound characteristics and dressing selection, but once a day cleansing is a minimum. Clean versus sterile technique for dressing changes is constantly debated with varying outcomes and supporting arguments. Most importantly, consider the host system defenses and type of wound when deciding whether to use a clean or sterile technique for dressing changes and cleansing.

Wound assessment involves many parameters, but the following indices should be included in continued documentation of wound healing: size (length, width, depth), extent of tissue involvement (partial or full thickness; stage of pressure ulcer), presence of undermining or tracts, anatomic location, type of tissue in base (viable or nonviable), color (red, yellow, black categories), exudate, edges, presence of foreign bodies, condition of surrounding skin, and duration. Photography is useful for documenting progress and should include a measuring scale and date.

Drawn from MedMarket Diligence report #S254,  “Wound Management to 2026”. Details.

Bioengineered Skin and Skin Substitutes, Sales and Growth, 2017 to 2026

The use of bioengineered skin and skin substitutes in the treatment of wounds is on a strong, but variable growth curve. Currently, the highest sales of these products in wound management occurs in the United States, where sales are in excess of $700 million annually already and growth in sales of these products is projected at or near 10% annually through 2026.

While China “only” has sales of just over $200 million in bioengineered skin and skin substitutes, the projected >20% CAGR to 2026 will result in China’s sales approximating U.S. sales in a decade.

Source: MedMarket Diligence, LLC; Report #S254.

Wound Care Market Shares Worldwide

Analyzing data from Report #S254 ,”Wound Management to 2026″, we present the distribution of top competitor’s sales in each segment in 2017. Smith & Nephew, Johnson & Johnson, and 3M dominate the global wound management, with varying dominance between them — or by other companies — in each segment.

Source: MedMarket Diligence, LLC; Report #s254. (Publishing March 2018)

S&N leads the global market, following closely by JNJ. Both companies are active in multiple segments of wound management. S&N has lower traditional wound management product sales (simple dressings and bandages) and higher sales of “advanced” wound management products. J&J does $800 million more sales in traditional dressings, gauze and bandages than S&N, but lesser involvement in newer wound technologies such as NPWT, bioengineered skin, and growth factors.

Source: MedMarket Diligence, LLC; Report #s254. (Publishing March 2018)


China, USA, and Japan Wound Markets

The distribution of sales of different wound management products naturally varies from one country to the next based on pricing, reimbursement, local clinical practice trends, cultural characteristics, and any number of other drivers. The net effect is different distributions.

The goal for wound market players in gauging opportunities is knowing where things are going.

In the global aggregate, here is how we anticipate the market for wound management products in 2016 will stack up compared to 2026:

Source: MedMarket Diligence, LLC; Report #S254.

As you can see, traditional wound management products are giving way in the balance to advanced products. How this global dynamic plays out differently in local markets is important for manufacturers to consider, as shown in the comparison of wound markets in China, the USA and Japan, both in 2017 and 2026.

Source: MedMarket Diligence, LLC; Report #S254.

You can see (in graph, above) the difference in relative sizes of the USA, Japan and China wound markets, in both 2017 and 2026. The largest relative increase in the absolute market will occur in China as a result of its double-digit growth rate. By comparison, the USA market overall is growing slightly faster than Japan (5.8% versus 4.2%, CAGR 2017-26).

Source: MedMarket Diligence, LLC; Report #S254.

More remarkable is the difference in distribution of products sold in these three countries. With the exception of a consistent general decline in relative sales of traditional products, each of these countries is exhibiting different rates of change in the distribution of wound product sales from 2017 to 2026.

March 2018
Worldwide Wound Management, Forecast to 2026:

Established and Emerging Products, Technologies and Markets in the Americas, Europe, Asia/Pacific and Rest of World.” Report #S254.


Country and Regional Variability in Growth of Wound Management Sales

As illustrated in a previous post, wound management products are a spectrum from the simple to the complex:

Source: MedMarket Diligence Report #S254.

Generally, the longer the product has been around (e.g., gauze), the less complex it is compared to emerging technologies…

…BUT simpler is easy to adopt and, with well established sales, growth on a percentage basis will be low (see area in red).

Generally, new technologies incorporate rarer materials, have more complex construction, and may cost considerably more…

…BUT complex technologies may be far more effective clinically than older technologies and may allow treatment where no older technology could, and with low initial sales (penetrated potential), growth on a percentage bases will be high (see area in green).

Country and Regional Variation in Growth Rates

While this size-to-growth dynamic exists for most product types, the dynamic varies from one geographic region to the next. The time point at which a particular product/technology starts to be more rapidly adopted — or the rate at which use of  established products are use starts to decline — can vary considerably from country to country.

As a result, there will be variability in sales growth rates for a product in one country/region versus another.

For example, the 2017 to 2026 compound annual growth rate in sales of Alginates in wound management range from a low of 5.3% in one country to a high of 24.3% in another country. (If you make alginates, in which country would YOU like to compete?)

Regionally, as in USA versus Europe versus Asia/Pacific, etc., there is less variation in growth rates for any given product in that region. For alginates:

country-to-country variation in CAGR: 19%
region-to-region variation in CAGR: 7.8%

In other words, the difference between the countries with the highest and lowest CAGRs for alginate sales is 19%, while the difference between regions shows one region with a 7.8% higher CAGR for alginates than the lowest growth region.

Source: MedMarket Diligence, LLC; Report #S254.

Before chasing after that high growth rate, it is important to know the underlying volume. (Sales of $1 in year 1 and $2 in year 2 is a 100% growth rate, but it’s absolute growth of only $1.)

See the full REPORT, “Wound Management to 2026” details or order online. Please also see the forecast and market share data available separately from the report.


The future of medicine in 2037

In the post below from 2016, we wrote of what we can expect for medicine 20 years into the future. We review and revise it anew here.

An important determinant of “where medicine will be” in 2035 is the set of dynamics and forces behind healthcare delivery systems, including primarily the payment method, especially regarding reimbursement. It is clear that some form of reform in healthcare will result in a consolidation of the infrastructure paying for and managing patient populations. The infrastructure is bloated and expensive, unnecessarily adding to costs that neither the federal government nor individuals can sustain. This is not to say that I predict movement to a single payer system — that is just one perceived solution to the problem. There are far too many costs in healthcare that offer no benefits in terms of quality; indeed, such costs are a true impediment to quality. Funds that go to infrastructure (insurance companies and other intermediaries) and the demands they put on healthcare delivery work directly against quality of care. So, in the U.S., whether the Affordable Care Act (“Obamacare”) persists (most likely) or is replaced with a single payer system, state administered healthcare (exchanges) or some other as-yet-unidentified form, there will be change in how healthcare is delivered from a cost/management perspective.  -[Editor’s note: After multiple attempts by the GOP to “repeal and replace”, the strengths of Obamacare have outweighed its weaknesses in the minds of voters who have thus voiced their opinions to their representatives, many seeking reelection in 2018.]

From the clinical practice and technology side, there will be enormous changes to healthcare. Here are examples of what I see from tracking trends in clinical practice and medical technology development:

  • Cancer 5 year survival rates will, for many cancers, be well over 90%. Cancer will largely be transformed in most cases to chronic disease that can be effectively managed by surgery, immunology, chemotherapy and other interventions. Cancer and genomics, in particular, has been a lucrative study (see The Cancer Genome Atlas). Immunotherapy developments are also expected to be part of many oncology solutions. Cancer has been a tenacious foe, and remains one we will be fighting for a long time, but the fight will have changed from virtually incapacitating the patient to following protocols that keep cancer in check, if not cure/prevent it.
    [Editor’s note: Immunology has surged in a wide range of cancer-related research yielding new weapons to cure cancer or render it to routine clinical management.]
  • Diabetes Type 1 (juvenile onset) will be managed in most patients by an “artificial pancreas”, a closed loop glucometer and insulin pump that will self-regulate blood glucose levels. OR, stem cell or other cell therapies may well achieve success in restoring normal insulin production and glucose metabolism in Type 1 patients. The odds are better that a practical, affordable artificial pancreas will developed than stem or other cell therapy, but both technologies are moving aggressively and will gain dramatic successes within 20 years.

Developments in the field of the “artificial pancreas” have recently gathered considerable pace, such that, by 2035, type 1 blood glucose management may be no more onerous than a house thermostat due to the sophistication and ease-of-use made possible with the closed loop, biofeedback capabilities of the integrated glucometer, insulin pump and the algorithms that drive it, but that will not be the end of the development of better options for type 1 diabetics. Cell therapy for type 1 diabetes, which may be readily achieved by one or more of a wide variety of cellular approaches and product forms (including cell/device hybrids) may well have progressed by 2035 to become another viable alternative for type 1 diabetics. [Editor’s note: Our view of this stands, as artificial pancreases are maturing in development and reaching markets. Cell therapy still offers the most “cure-like” result, which is likely to happen within the next 20 years.]

  • Diabetes Type 2 (adult onset) will be a significant problem, governed as it is by different dynamics than Type 1. A large body of evidence will exist that shows dramatically reduced incidence of Type 2 associated with obesity management (gastric bypass, satiety drugs, etc.) that will mitigate the growing prevalence of Type 2, but research into pharmacologic or other therapies may at best achieve only modest advances. The problem will reside in the complexity of different Type 2 manifestation, the late onset of the condition in patients who are resistant to the necessary changes in lifestyle and the global epidemic that will challenge dissemination of new technologies and clinical practices to third world populations.

Despite increasing levels of attention being raised to the burden of type 2 worldwide, including all its sequellae (vascular, retinal, kidney and other diseases), the pace of growth globally in type 2 is still such that it will represent a problem and target for pharma, biotech, medical device, and other disciplines. [Editor’s note: the burden of Type 2 on people, families, communities, and governments globally should motivate policy, legislation, and other action, but global initiatives have a long way to travel.]

  • Cell therapy and tissue engineering will offer an enormous number of solutions for conditions currently treated inadequately, if at all. Below is an illustration of the range of applications currently available or in development, a list that will expand (along with successes in each) over the next 20 years.

    Cell therapy will have deeply penetrated virtually every medical specialty by 2035. Most advanced will be those that target less complex tissues: bone, muscle, skin, and select internal organ tissues (e.g., bioengineered bladder, others). However, development will have also followed the money. Currently, development and use of conventional technologies in areas like cardiology, vascular, and neurology entails high expenditure that creates enormous investment incentive that will drive steady development of cell therapy and tissue engineering over the next 20 years, with the goal of better, more long-term and/or less costly solutions.
  • Gene therapy will be an option for a majority of genetically-based diseases (especially inherited diseases) and will offer clinical options for non-inherited conditions. Advances in the analysis of inheritance and expression of genes will also enable advanced interventions to either ameliorate or actually preempt the onset of genetic disease.

    As the human genome is the engineering plans for the human body, it is a potential mother lode for the future of medicine, but it remains a complex set of plans to elucidate and exploit for the development of therapies. While genetically-based diseases may readily be addressed by gene therapies in 2035, the host of other diseases that do not have obvious genetic components will resist giving up easy gene therapy solutions. Then again, within 20 years a number of reasonable advances in understanding and intervention could open the gate to widespread “gene therapy” (in some sense) for a breadth of diseases and conditions. [Editor’s note: CRISPR and other gene-editing techniques have accelerated the pace at which practical and affordable gene-therapies will reach the market.]
  • Drug development will be dramatically more sophisticated, reducing the development time and cost while resulting in drugs that are far more clinically effective (and less prone to side effects). [Editor’s note: We are revising our optimism about drug development being more sophisticated and streamlined. To a measurable degree, “distributed processing systems” have proven far more exciting in principle than practice, since results — marketable drugs derived this way — have been scant. We remain optimistic as a result of the rapid emergence of artificial intelligence (AI) and deep learning, which have have very credible promise to impact swaths of industry, especially in medicine.]
    This arises from drug candidates being evaluated via distributed processing systems (or quantum computer systems) that can predict efficacy and side effect without need of expensive and exhaustive animal or human testing.The development of effective drugs will have been accelerated by both modeling systems and increases in our understanding of disease and trauma, including pharmacogenomics to predict drug response. It may not as readily follow that the costs will be reduced, something that may only happen as a result of policy decisions.

  • Most surgical procedures will achieve the ability to be virtually non-invasive. Natural orifice transluminal endoscopic surgery (NOTES) will enable highly sophisticated surgery without ever making an abdominal or other (external) incision. Technologies like “gamma knife” and similar will have the ability to destroy tumors or ablate pathological tissue via completely external, energy-based systems. [Editor’s note: In the late 1980s, laparoscopy revolutionized surgery for its less invasiveness. Now, NOTES procedures and external energy technologies (e.g., gamma knife) have now proven to be about as minimally invasive as medical devices can be. To be even less invasive will require development of drugs (including biotechs) that succeed as therapeutic alternatives to any kind of surgery.]

    By 2035, technologies such as these will measurably reduce inpatient stays, on a per capita basis, since a significant reason for overnight stays is the trauma requiring recovery, and eliminating trauma is a major goal and advantage of minimally invasive technologies (e.g., especially the NOTES technology platform). A wide range of other technologies (e.g., gamma knife, minimally invasive surgery/intervention, etc.) across multiple categories (device, biotech, pharma) will also have emerged and succeeded in the market by producing therapeutic benefit while minimizing or eliminating collateral damage.

  • Information technology will radically improve patient management. Very sophisticated electronic patient records will dramatically improve patient care via reduction of contraindications, predictive systems to proactively manage disease and disease risk, and greatly improve the decision-making of physicians tasked with diagnosing and treating patients.There are few technical hurdles to the advancement of information technology in medicine, but even in 2035, infotech is very likely to still be facing real hurdles in its use as a result of the reluctance in healthcare to give up legacy systems and the inertia against change, despite the benefits. [Editor’s note: Before AI and other systems will truly have an impact, IT and its policy for healthcare in the next 10 years will solve the problem of health data residing inertly behind walls that hinder efficient use of the rich, patient-specific knowledge that physicians and healthcare systems might use to improve the quality and cost of care.]
  • Personalized medicine. Perfect matches between a condition and its treatment are the goal of personalized medicine, since patient-to-patient variation can reduce the efficacy of off-the-shelf treatment. The thinking behind gender-specific joint replacement has led to custom-printed 3D implants. The use of personalized medicine will also be manifested by testing to reveal potential emerging diseases or conditions, whose symptoms may be ameliorated or prevented by intervention before onset.
  • Systems biology will underlie the biology of most future medical advances in the next 20 years. Systems biology is a discipline focused on an integrated understanding of cell biology, physiology, genetics, chemistry, and a wide range of other individual medical and scientific disciplines. It represents an implicit recognition of an organism as an embodiment of multiple, interdependent organ systems and its processes, such that both pathology and wellness are understood from the perspective of the sum total of both the problem and the impact of possible solutions.This orientation will be intrinsic to the development of medical technologies, and will increasingly be represented by clinical trials that throw a much wider and longer-term net around relevant data, staff expertise encompassing more medical/scientific disciplines, and unforeseen solutions that present themselves as a result of this approach.Other technologies being developed aggressively now will have an impact over the next twenty years, including medical/surgical robots (or even biobots), neurotechnologies to diagnose, monitor, and treat a wide range of conditions (e.g., spinal cord injury, Alzheimer’s, Parkinson’s etc.).

The breadth and depth of advances in medicine over the next 20 years will be extraordinary, since many doors have been recently opened as a result of advances in genetics, cell biology, materials science, systems biology and others — with the collective advances further stimulating both learning and new product development. 

See Reports:

Report #290, “Worldwide Markets for Medical and Surgical Sealants, Glues, and Hemostats, 2015-2022.”

Report #S254, “Wound Management to 2026.”

Naturally sticky: Biologically-based medical glues dominate

Medical glues are either biologically-based, cyanoacrylate, or other synthetic. The bulk of global sales of medical glues are biologically-based, (includes fibrin, thrombogen, and others), cyanoacrylate-based glues, and other synthetic glues.

Cyanoacrylate-based glues, include those from Ethicon, Adhezion Biomedical, B. Braun, Meyer-Haake, and others. Cyanoacrylates provide strong adhesion, but biologically-based glues have found more applications, both topically and internally. “Other” glues are of a variety of synthetic types; these glues have yet to gain more than 4% share globally.

Below is illustrated the growth of biologically-based glues by region, showing that most growth in this segment will be from Asia/Pacific markets, which are consistently demonstrating higher growth than in western markets.

Global Markets for Biologically-Based Medical Glues, 2015-2022, USD MillionsSource: MedMarket Diligence, LLC; Report #S290. (Order online)


Medtech fundings for March 2017

Medtech fundings for March 2017 totaled over $2 billion, led by the $1.2 billion raise by ConvaTec, the $59 million IPO of Symetics, the $50 million Series C funding of Moximed, the $45 million funding of Corindus, and the $40 million funding round of VertiFlex.

The complete list of fundings in medtech for March 2017 are shown at link. Below are the top fundings for the month.

Source: Compiled by MedMarket Diligence, LLC

For a historical list of fundings by month since 2009, see link.

Factors Affecting Wound Healing

Coming March 2018:  Worldwide Wound Management, Forecast to 2026 more

The below is excerpted from Wound Management Report #S251

A delicate physiological balance must be maintained during the healing process to ensure timely repair or regeneration of damaged tissue. Wounds may fail to heal or have a greatly increased healing time when unfavorable conditions are allowed to persist. An optimal environment must be provided to support the essential biochemical and cellular activities required for efficient wound healing and to remove or protect the wound from factors that impede the healing process.

Factors affecting wound healing may be considered in one of two categories depending on their source. Extrinsic factors impinge on the patient from the external environment, whereas intrinsic factors directly affect the performance of bodily functions through the patient’s own physiology or condition.

Wound bed preparation (WBP) is essential for the support of efficient and effective healing, especially when advanced wound care products are to be used. WBP involves removing localized barriers to healing, such as exudate, dead tissue or infected tissue.

Wound Bed Preparation: the TIME and DIMES acronyms

WBP involves debridement, reduction and neutralization of the bioburden and management of exudate from the wound. The TIME acronym provides a systematic way to manage wounds by looking at each stage of wound healing. The goal is to have the best, thoroughly-vascularized wound bed possible.

TIME stands for:

  • T: Tissue, non-viable or deficient.

The wound care professional should look for non-viable tissue, which includes necrotic tissue, tissue which has sloughed off, or non-viable tendon or bone.

  • I: Infection or Inflammation

Examine the wound for infection, inflammation or other signs of infection. Are there clinical signs that there may be a problem with bacterial bioburden?

  • M: Moisture Balance

Is the wound too dry, or does it have excess exudate?

What is the objective of topical therapy: absorption or drainage?

  • E: Edge of wound—non-advancing or undermined

Examine the edges of the wound. Are the edges undermined, or is the epidermis failing to migrate across the granulation tissue?

The DIMES acronym is very similar to TIME:

  • Debridement (autolytic)

For wounds with the ability to heal, adequate and repeated debridement is an important first step in removing necrotic tissue. Debridement may also help healing by removing both senescent cells that are no longer capable of normal cellular activities and biofilms that may be shielding bacterial colonies.

  • Infection/Inflammation

The level of bacterial damage may include contamination (organisms present), colonization (organisms present which may cause surface damage if critically colonized) or infection. Treatment needs to make a match between the individual patient’s wound and the appropriate product.

  • Moisture balance

Clinicians need to create a careful balance in the wound such that the environment is neither too wet nor too dry. The environment itself will change as the wound heals.

  • Edge/Environment

The clinician should carefully examine and monitor the wound edge. If the wound edge is not migrating after appropriate wound bed preparation, and if healing appears to be stalled, then more advanced wound care therapies should be considered.

  • Supportive Products and Services

There are additional products which support wound healing yet don’t fall into one of these steps. For example, proper nutritional support is important to achieving the goal of a fully healed wound.

Extrinsic Factors

Extrinsic factors affecting wound healing include:

  • Mechanical stress
  • Debris
  • Temperature
  • Desiccation and maceration
  • Infection
  • Chemical stress
  • Medications
  • Other factors such as alcohol abuse, smoking, and radiation therapy

Mechanical Stress

Mechanical stress factors include pressure, shear, and friction. Pressure can result from immobility, such as experienced by a bed- or chair-bound patient, or local pressures generated by a cast or poorly fitting shoe on a diabetic foot. When pressure is applied to an area for sufficient time and duration, blood flow to the area is compromised and healing cannot take place. Shear forces may occlude blood vessels, and disrupt or damage granulation tissue. Friction wears away newly formed epithelium or granulation tissue and may return the wound to the inflammatory phase.


Debris, such as necrotic tissue or foreign material, must be removed from the wound site in order to allow the wound to progress from the inflammatory stage to the proliferative stage of healing. Necrotic debris includes eschar and slough. The removal of necrotic tissue is called debridement and may be accomplished by mechanical, chemical, autolytic, or surgical means. Foreign material may include sutures, dressing residues, fibers shed by dressings, and foreign material which were introduced during the wounding process, such as dirt or glass.


Temperature controls the rate of chemical and enzymatic processes occurring within the wound and the metabolism of cells and tissue engaged in the repair process. Frequent dressing changes or wound cleansing with room temperature solutions may reduce wound temperature, often requiring several hours for recovery to physiological levels. Thus, wound dressings that promote a “cooling” effect, while they may help to decrease pain, may not support wound repair.

Desiccation and Maceration

Desiccation of the wound surface removes the physiological fluids that support wound healing activity. Dry wounds are more painful, itchy, and produce scab material in an attempt to reduce fluid loss. Cell proliferation, leukocyte activity, wound contraction, and revascularization are all reduced in a dry environment. Epithelialization is drastically slowed in the presence of scab tissue that forces epithelial cells to burrow rather than freely migrate over granulation tissue. Advanced wound dressings provide protection against desiccation.

Maceration resulting from prolonged exposure to moisture may occur from incontinence, sweat accumulation, or excess exudates. Maceration can lead to enlargement of the wound, increased susceptibility to mechanical forces, and infection. Advanced wound products are designed to remove sources of moisture, manage wound exudates, and protect skin at the edges of the wound from exposure to exudates, incontinence, or perspiration.


Infection at the wound site will ensure that the healing process remains in the inflammatory phase. Pathogenic microbes in the wound compete with macrophages and fibroblasts for limited resources and may cause further necrosis in the wound bed. Serious wound infection can lead to sepsis and death. While all ulcers are considered contaminated, the diagnosis of infection is made when the wound culture demonstrates bacterial counts in excess of 105 microorganisms per gram of tissue. The clinical signs of wound infection are erythema, heat, local swelling, and pain.

Chemical Stress

Chemical stress is often applied to the wound through the use of antiseptics and cleansing agents. Routine, prolonged use of iodine, peroxide, chlorhexidine, alcohol, and acetic acid has been shown to damage cells and tissue involved in wound repair. Their use is now primarily limited to those wounds and circumstances when infection risk is high. The use of such products is rapidly discontinued in favor of using less cytotoxic agents, such as saline and nonionic surfactants.


Medication may have significant effects on the phases of wound healing. Anti-inflammatory drugs such as steroids and non-steroidal anti-inflammatory drugs may reduce the inflammatory response necessary to prepare the wound bed for granulation. Chemotherapeutic agents affect the function of normal cells as well as their target tumor tissue; their effects include reduction in the inflammatory response, suppression of protein synthesis, and inhibition of cell reproduction. Immunosuppressive drugs reduce WBC counts, reducing inflammatory activities and increasing the risk of wound infection.

Other Extrinsic Factors

Other extrinsic factors that may affect wound healing include alcohol abuse, smoking, and radiation therapy. Alcohol abuse and smoking interfere with body’s defense system, and side effects from radiation treatments include specific disruptions to the immune system, including suppression of leukocyte production that increases the risk of infection in ulcers. Radiation for treatment of cancer causes secondary complications to the skin and underlying tissue. Early signs of radiation side effects include acute inflammation, exudation, and scabbing. Later signs, which may appear four to six months after radiation, include woody, fibrous, and edematous skin. Advanced radiated skin appearances can include avascular tissue and ulcerations in the circumscribed area of the original radiation. The radiated wound may not become evident until as long as 10-20 years after the end of therapy.

Intrinsic Factors

Intrinsic factors that directly affect the performance of healing are:

  • Health status
  • Age factors
  • Body build
  • Nutritional status

Health Status

Chronic diseases, such as circulatory conditions, anemias and autoimmune diseases, influence the healing process as a result of their influence on a number of bodily functions. Illnesses that cause the most significant problems include diabetes, chronic obstructive pulmonary disease (COPD), arteriosclerosis, peripheral vascular disease (PVD), heart disease, and any conditions leading to hypotension, hypovolemia, edema, and anemia. While chronic diseases are more frequent in the elderly, wound healing will be delayed in any patient with a pre-existing underlying illness.

Chronic circulatory diseases which reduce blood flow, such as arterial or venous insufficiency, lower the amount of oxygen available for normal tissue activity and replacement. Anemias such as sickle-cell anemia result in reduced delivery of oxygen to tissues and decreased ability to support wound healing.

Normal immune function is required during the inflammatory phase by providing the WBCs (white blood cells) that orchestrate or coordinate the normal sequence of events in wound healing. Autoimmune diseases such as lupus and rheumatoid arthritis interfere with normal collagen deposition, and impair granulation.

Diabetes is associated with delayed cellular response to injury, compromised cellular function at the site of injury, defects in collagen synthesis, and reduced wound tensile strength after healing. Diabetes-related peripheral neuropathy (DPN), which reduces the ability to feel pressure or pain, contributes to a tendency to ignore pressure points and avoid pressure relief strategies.

Acquired Immune Deficiency Syndrome

Patients with acquired immunodeficiency syndrome (AIDS) have significant impact on the wound healing market as their numbers rise and their average life expectancy increases. Patients in the latter stages of the disease experience drastic reductions in mobility, activity, and nutritional status, placing them at high risk for the development of pressure ulcers. Minor scrapes or abrasions are at high risk for infection and may progress to full-thickness wounds requiring antibiotic therapy and aggressive wound management. Skin tumors, such as Kaposi’s sarcoma, lead to surgical incisions closed by secondary intention requiring the use of appropriate dressings.

The skin of AIDS patients becomes drier as the syndrome progresses. As the CD4+ T cell count falls below 400/mm3, pruritus increases and erythematous patches appear on the skin, progressing to ichthyosis and appearing as large polygonal scales, especially on the lower limbs. Histological changes include hyperkeratosis and thinning of the granular layer of the epidermis. As skin becomes more fragile, care must be exercised in the selection of tapes and adhesive dressings to avoid skin stripping and skin tears.

Age Factors

Observable changes in wound healing in the elderly include increased time to heal and the fragile structure of healed wounds. Delays are speculated to be the result of a general slowing of metabolism and structural changes in the skin of elderly people. Structural changes include a flattening of the dermal-epidermal junction that often leads to skin tears, reduced quality and quantity of collagen, reduced padding over bony prominences, and reduction in the intensity of the immune response.

Body Build

Body build can affect the delivery and availability of oxygen and nutrients at the wound site. Underweight individuals may lack the necessary energy and protein reserves to provide sufficient raw materials for proliferative wound healing. Bony prominences lack padding and become readily susceptible to pressure due to the reduced blood supply of wounds associated with bony prominences. Poor nutritional habits and reduced mobility of overweight individuals lead to increased risk of wound dehiscence, hernia formation, and infection.

Nutritional Status

Healing wounds, especially full-thickness wounds, require an adequate supply of nutrients. Wounds require calories, fats, proteins, vitamins and minerals, and adequate fluid intake. Calories provide energy for all cellular activity, and when in short supply in the diet, the body will utilize stored fat and protein. The metabolism of these stored substances causes a reduction in weight and changes in pressure distribution through reduction of adipose and muscle padding. Sufficient dietary calories maintain padding and ensure that dietary protein and fats are available for use in wound healing. In addition, adequate levels of protein are necessary for repair and replacement of tissue. Increased protein intake is particularly important for wounds where there is significant tissue loss requiring the production of large amounts of connective tissue. Protein deficiencies have been associated with poor revascularization, decreased fibroblast proliferation, reduced collagen formation, and immune system deficiencies.

Reduced availability of vitamins, minerals, and trace elements will also affect wound healing. Vitamin C is required for collagen synthesis, fibroblast functions, and the immune response. Vitamin A aids macrophage mobility and epithelialization. Vitamin B complex is necessary for the formation of antibodies and WBCs, and Vitamin B or thiamine maintains metabolic pathways that generate energy required for cell reproduction and migration during granulation and epithelialization. Iron is required for the synthesis of hemoglobin, which carries oxygen to the tissues, and copper and zinc play a role in collagen synthesis and epithelialization.

Adequate nutrition is an often-overlooked requirement for normal wound healing. Inadequate protein-calorie nutrition, even after just a few days of starvation, can impair normal wound-healing mechanisms. For healthy adults, daily nutritional requirements are approximately 1.25-1.5 g of protein per kilogram of body weight and 30-35 calories/kg.  These requirements should be increased for those with sizable wounds.

Malnutrition should be suspected in patients presenting with chronic illnesses, inadequate societal support, multisystem trauma, or GI or neurologic problems that may impair oral intake. Protein deficiency occurs in about 25% of all hospitalized patients.

Chronic malnutrition can be diagnosed by using anthropometric data to compare actual and ideal body weights and by observing low serum albumin levels. Serum prealbumin is sensitive for relatively acute malnutrition because its half-life is 2-3 days (vs 21 d for albumin). A serum prealbumin level of less than 7 g/dL suggests severe protein-calorie malnutrition.

Vitamin and mineral deficiencies also require correction. Vitamin A deficiency reduces fibronectin on the wound surface, reducing cell chemotaxis, adhesion, and tissue repair. Vitamin C is required for the hydroxylation of proline and subsequent collagen synthesis.

Vitamin E, a fat-soluble antioxidant, accumulates in cell membranes, where it protects polyunsaturated fatty acids from oxidation by free radicals, stabilizes lysosomes, and inhibits collagen synthesis. Vitamin E inhibits prostaglandin synthesis by interfering with phospholipase-A2 activity and is therefore anti-inflammatory. Vitamin E supplementation may decrease scar formation.

Zinc is a component of approximately 200 enzymes in the human body, including DNA polymerase, which is required for cell proliferation, and superoxide dismutase, which scavenges superoxide radicals produced by leukocytes during debridement.

From, “Worldwide Wound Management, Forecast to 2026: Established and Emerging Products, Technologies and Markets in the Americas, Europe, Asia/Pacific and Rest of World”. Report #S254. Available online.

Cardiovascular procedure volume growth (interventional and surgical)

Cardiovascular surgical and interventional procedures are performed to treat conditions causing inadequate blood flow and supply of oxygen and nutrients to organs and tissues of the body. These conditions include the obstruction or deformation of arterial and venous pathways, distortion in the electrical conducting and pacing activity of the heart, and impaired pumping function of the heart muscle, or some combination of circulatory, cardiac rhythm, and myocardial disorders. Specifically, these procedures are:

  • Coronary artery bypass graft (CABG) surgery;
  • Coronary angioplasty and stenting;
  • Lower extremity arterial bypass surgery;
  • Percutaneous transluminal angioplasty (PTA) with and without bare metal and drug-eluting stenting;
  • Peripheral drug-coated balloon angioplasty;
  • Peripheral atherectomy;
  • Surgical and endovascular aortic aneurysm repair;
  • Vena cava filter placement
  • Endovenous ablation;
  • Mechanical venous thrombectomy;
  • Venous angioplasty and stenting;
  • Carotid endarterectomy;
  • Carotid artery stenting;
  • Cerebral thrombectomy;
  • Cerebral aneurysm and AVM surgical clipping;
  • Cerebral aneurysm and AVM coiling & flow diversion;
  • Left Atrial Appendage closure;
  • Heart valve repair and replacement surgery;
  • Transcatheter valve repair and replacement;
  • Congenital heart defect repair;
  • Percutaneous and surgical placement of temporary and permanent mechanical cardiac support devices;
  • Pacemaker implantation;
  • Implantable cardioverter defibrillator placement;
  • Cardiac resynchronization therapy device placement;
  • Standard SVT & VT ablation; and
  • Transcatheter AFib ablation

For 2016 to 2022, the total worldwide volume of these cardiovascular procedures is forecast to expand on average by 3.7% per year to over 18.73 million corresponding surgeries and transcatheter interventions in the year 2022. The largest absolute gains can be expected in peripheral arterial interventions (thanks to explosive expansion in utilization of drug-coated balloons in all market geographies), followed by coronary revascularization (supported by continued strong growth in Chinese and Indian PCI utilization) and endovascular venous interventions (driven by grossly underserved patient caseloads within the same Chinese and Indian market geography).

Venous indications are also expected to register the fastest (5.1%) relative procedural growth, followed by peripheral revascularization (with 4.0% average annual advances) and aortic aneurysm repair (projected to show a 3.6% average annual expansion).

Source: MedMarket Diligence, LLC; “Global Dynamics of Surgical and Interventional Cardiovascular Procedures, 2015-2022,” (Report #C500).

Geographically, Asian-Pacific (APAC) market geography accounts for slightly larger share of the global CVD procedure volume than the U.S. (29.5% vs 29,3% of the total), followed by the largest Western European states (with 23.9%) and ROW geographies (with 17.3%). Because of the faster growth in all covered categories of CVD procedures, the share of APAC can be expected to increase to 33.5% of the total by the year 2022, mostly at the expense of the U.S. and Western Europe.

However, in relative per capita terms, covered APAC territories (e.g., China and India) are continuing to lag far behind developed Western states in utilization rates of therapeutic CVD interventions with roughly 1.57 procedures per million of population performed in 2015 for APAC region versus about 13.4 and 12.3 CVD interventions done per million of population in the U.S. and largest Western European countries.

Source: MedMarket Diligence, LLC; “Global Dynamics of Surgical and Interventional Cardiovascular Procedures, 2015-2022,” (Report #C500).

Global Cardiovascular Procedures report #C500 details the current and projected surgical and interventional therapeutic procedures commonly used in the management of acute and chronic conditions affecting myocardium and vascular system.